PROJECT SUMMARY Sturge-Weber syndrome (SWS) is a sporadic neurocutaneous disorder characterized by a facial port-wine birthmark and leptomeningeal vascular malformation (LVM). SWS most often (85%) affects one cerebral hemisphere and has a progressive but highly variable clinical course, thus providing a unique clinical model to study the neurocognitive effects of an early, postnatal, unilateral brain lesion. Most children with SWS develop seizures during the first 2 years of life and also develop neurological symptoms as well as cognitive impairment. Currently, SWS has no cure or specific treatment. With NIH support and nationwide patient recruitment, we have built a clinical imaging research program for children with SWS, in order to understand the pathophysiology of progression and find new diagnostic and treatment paradigms. We have tested novel MRI approaches for more accurate detection of SWS-related brain abnormalities and identified critical age windows when most of the progressive brain damage occurs. Recently, we have also identified two, potentially powerful compensatory mechanisms that may prevent severe neurocognitive complications of SWS-related brain injury: (i) a deep venous vascular remodeling in the ipsilateral (SWS-affected) hemisphere, and (ii) reorganization in the contralateral hemisphere affecting both verbal and non-verbal cognitive functions. We also identified a subgroup of children with SWS whose cognitive functions improved over time, presumably due to effective compensatory processes. In Aim 1 of this renewal proposal, we will test the application of a recently developed rapid MRI protocol (called STAGE) for safe and accurate early screening and late follow-up of brain vascular and parenchymal abnormalities. This new, innovative imaging approach is widely applicable and could change clinical practice for SWS imaging, used as a screening technique in preventive trials, and be utilized in other pediatric neurological diseases. In Aim 2, we will extend our previous studies to older children and young adults with SWS to use susceptibility-weighted imaging and diffusion tensor imaging connectivity studies to evaluate the role of vascular remodeling and structural brain reorganization, respectively, in the preservation and reorganization of motor symptoms and specific cognitive functions that can be targeted by interventions. In Aim 3, we will use SWS epilepsy surgical tissue to harvest cells from both the LVM and various parenchymal cells and utilize a laser capture microdissection approach to identify specific cell types harboring the somatic GNAQ mutation. We will also study the imaging correlates and associated protein changes associated with dysregulated angiogenesis. The expected findings could fundamentally shape our concept as to how this mutation can lead to brain pathology and will also identify novel treatment targets.